Analysis of online prescription patterns in Chinese patients with sequelae of cerebral infarction: a real-world study

Cerebral infarction (CI) is a common cerebrovascular disease worldwide, and the burden caused by the sequelae of CI has increased significantly. However, current treatment guidelines lack standardized recommendations for pharmacotherapy of sequelae of CI. This retrospective study collected and analyzed 1.98 million prescriptions concerning sequelae of CI from patients admitted to Zhiyun Health Internet Hospital in 2022. The mean age of patients was 66.2 ± 11.4 years, and 52.40% were male. 79.73% had one or more comorbidities. For treatment, the prescriptions of 1-, 2- and ≥ 3-drug accounted for 64.55%, 23.77% and 11.68% respectively. Chinese patent medicine (CPM) prescriptions, western medicine (WM) prescriptions, and CPM and WM combined (CPM + WM) prescriptions accounted for 53.81%, 27.33%, and 18.86% respectively. In CPM prescriptions, the most frequently prescribed medications were Salvia miltiorrhiza (34.81%), Ginkgo biloba (24.96%), Panax notoginseng (20.67%), Gastrodia (7.15%) and Ligusticum Wallichii (4.90%). For WM prescriptions, the most commonly prescribed agents were anti-hypertensive (32.82%), anti-thrombotic (16.06%), vasodilator (15.70%), anti-dementia (10.88%), and lipid-lowering (9.58%) drugs. Among CPM + WM prescriptions, 72.61% had CPM/WM = 1, 21.20% had CPM/WM < 1, and 6.19% had CPM/WM > 1. This research utilized real-world data extracted from internet hospitals in China to present valuable evidence of online prescription patterns among patients experiencing sequelae of CI.


Patients
The study focused on patients with sequelae of CI, who had received specific medication recommendations for the management of this condition.All participants in the study had previously been diagnosed with sequelae of CI in public or private primary healthcare facilities.Patients were eligible for inclusion if they were aged 18 years or older, had been diagnosed with sequelae of CI, had received a prescription for the first time on the online platform between Jan 2022 and Dec 2022, and had comorbidities associated with sequelae of CI (determined based on the diagnostic information provided in the prescriptions).

Ethical consideration
Ethical assessment is not required prior to conducting the research reported in this paper, as the present study does not have experiments on human subjects and animals, and does not contain any sensitive and private information.The study used a database provided by Zhiyun Health Internet Hospital, and all data were encrypted to preserve patient privacy and confidentiality.This measure ensured that no individual's health data could be linked to specific individual.As per the Ethical Guidelines issued by the Office of the Medical Ethics Expert Committee of the National Health Care Commission of China, ethical approval and informed consent were not required for this study.All methods were carried out in accordance with relevant guidelines and regulations.

Statistical analysis
Data was retrieved using structured query language, and variables such as patient diagnosis, gender, age, and medication categories were analyzed.The first online prescription for sequelae of CI between Jan 2022 and Dec 2022 was considered the index prescription, with the endpoint being the proportion of index prescriptions during the period.Prescriptions were categorized based on the presence of CPM and WM in the prescriptions.Mean ± standard deviation was used to present patient age, total number of medications, and other data.Categorical data, including gender, prescription patterns, and comorbidities, were presented as numbers and percentages.Python 3.7 was used for all statistical analysis.

Clinical characteristics of cerebrovascular disease patients
Table 1 presents the clinical characteristics of patients with sequelae of CI.A total of 198,1450 valid prescriptions met the inclusion criteria for this retrospective study, and the average age of the patients was 66.2 ± 11.4 years.Among all the valid prescriptions, approximately 1.04 million were for male patients (52.40%).20.27% of patients had no comorbidity, while 79.73% had at least one comorbidities.In all the patients, hypertension emerged as the most frequent comorbidity, occurring in 51.26% of the patients, followed by diabetes (29.04%), chronic kidney disease (27.38%), dyslipidemia (16.12%), and coronary artery disease (8.69%).
The gender and age distribution of the patients with sequelae of CI is shown in Table 2.In the total population, the youngest age was 18 years and the oldest was 96 years.Among them, a large majority of participants were > 65 years old, accounting for 61.58% of the patients.

Prescription pattern
All the prescriptions were divided into different types according to the number of drugs.The most common type was 1-drug regimen (64.55%), followed by 2-drug combination regimen (23.77%), and ≥ 3-drug combination regimen (11.68%) (Fig. 3).
Table 5. Proportion of each class of western medicine in WM prescriptions.Vasodilators were vasodilators except antihypertensive drugs, such as nitrates.Others included medications for Parkinson's disease (60.58%), epilepsy (23.34%), and so on.

Western medicine Rate
Anti

Pattern of combination regimens
In the context of combination regimens, three primary forms were identified: WM + WM, CPM + WM, and CPM + CPM.Notably, CPM + WM emerged as the most common combination for both 2-drug and 3-drug combination regimens, representing 56.40% and 66.99% of prescriptions, respectively.Whereas CPM + CPM was the most commonly used in ≥ 4-drug combinations, accounting for 58.28% (Fig. 4).Due to the small proportion of ≥ 4-drug combinations, no further analysis of specific drug combinations was conducted.

Discussion
The study aimed to understand the drug prescription patterns of individuals with sequelae of CI by investigating prescriptions based on a real-world database and conducting big data analysis.The average age of all patients was 66.2 ± 11.4 years, with a slightly higher proportion of males (52.40%).These baseline findings are consistent with epidemiological studies on CI 12 .In addition, it is well established that hypertension is a major risk factor contributing to stroke DALYs 13 , and in this study, it emerged as the most common comorbidity associated with the sequelae of CI, accounting for 51.26% of cases.
CPM has been used for a long time as a common treatment in the management of the sequelae of CI, despite the lack of specific guideline recommendations.In this study, the CPMs that accounted for a higher percentage of statistical results were Salvia miltiorrhiza-based CPM, Ginkgo biloba-based CPM, and Panax notoginseng-based CPM.The efficacy of CPMs has been demonstrated in several clinical trials or basic research studies.For example, in a multicenter RCT, 2,200 patients with a history of ischemic stroke were randomized 1:1 to receive either Naoxintong capsule (Salvia miltiorrhiza-based CPM) or placebo in addition to standard care.Compared with the placebo group, the recurrence rate of ischemic stroke within 2 years was significantly lower in the Naoxintong group (P = 0.008), without increasing the risk of major bleeding in high-risk patients 14 .A systematic review and meta-analysis of 15 RCTs found that Ginkgo biloba extract (GBE, Ginkgo biloba-based CPM) improves neurological function and dependency in patients with different stages of ischemic stroke compared with conventional therapy and is generally safe for clinical use.The addition of GBE to conventional therapy improves Barthel Index scores and reduces neurological deficit scores in patients with acute ischemic stroke.In patients recovering from ischemic stroke (IS) or in the postictal period, GBE was superior to controls in improving dependency and neurological deficit scores 15 .An animal study shows that Xuesaitong (Panax notoginseng-based CPM) reduces brain infarct volume and alleviates neurological impairment 14 days after middle cerebral artery occlusion (MCAO), possibly by regulating microglial phenotypes via downregulation of the STAT3 signaling pathway 16 .
According to the theory of traditional Chinese medicine, patients in the sequelae stage of cerebral infarction often show the syndrome of qi deficiency and blood stasis, obstruction of meridians.Chinese patent medicines for promoting blood circulation, removing blood stasis and activating meridians can be appropriately selected 17 , such as Salvia miltiorrhiza-based CPM, Panax notoginseng-based CPM and Ginkgo biloba-based CPM.
Evidence-based practice guideline on integrative medicine for stroke 18 , focusing on the integrative approach of Western and Traditional Chinese Medicine (TCM) for stroke, is applicable across all levels of medical and rehabilitation institutions.It highlights the widespread use of this integrated approach in stroke prevention and treatment in China.Based on routine nursing and treatment, the addition of Chinese patent medicines has been shown to improve neurological damage in patients with IS.Initiating their use during the acute phase and continuing for 3-30 days may yield even greater benefits.Promising candidates include those CPMs made from Salvia miltiorrhiza, Ginkgo biloba, and Panax notoginseng.For patients with IS receiving internal medical treatment within 6 h of onset and without contraindications, in addition to intravenous thrombolysis, the immediate initiation of blood-activating and stasis-resolving TCM therapies can enhance neurological recovery.When combined with routine care and treatment after hemorrhage has been stabilized, TCM that activates blood and resolves stasis can also alleviate neurological deficits in patients with IS experiencing hemorrhagic transformation.
Although our study did not observe clinical effects or clinical outcomes, many previous studies have confirmed that CPM combined with WM can further improve the benefits of patients with CI or sequelae of CI.For example, in the treatment of CI, Xuesaitong (Panax notoginseng-based CPM) plus conventional treatment is conditionally recommended for the treatment of acute cerebral infarction to improve the total effective rate, National Institutes of Health Stroke Scale (NIHSS) score, China stroke scale (CSS) score, plasma viscosity (PV), and no serious adverse reactions were reported 19 .A systematic review and meta-analysis of 21 RCTs revealed that the combination of Salvianolate injection (Salvia miltiorrhiza-based CPM) with WM was associated with a higher overall response rate in the treatment of cerebral infarction compared to WM alone.Salvianolate injection demonstrated a positive impact on improving motor and cognitive functions without increasing adverse events 20 .In the treatment of CI sequela, when treating post-stroke epilepsy, a combination of oral Chinese herbal medicine and conventional WM outperformed WM monotherapy, reducing the duration of epileptic seizures and increasing the overall response rate 21 .Compared with standard WM treatment, TCM combined with WM treatment has a better effect on improving post-stroke depression (PSD) 22 .A meta-analysis of 1,367 patients with PSD from 18 RCTS showed that the combined treatment group exhibited improved scores on the Hamilton depression scale (HAMD), scores on the stroke scale (SSS), and enhanced Barthel index (BI) scores compared to the WM alone group.Additionally, gastrointestinal or neurological adverse events were also reduced in the combined treatment group 23 .A meta-analysis study of 8 RCTs involving 682 patients with neurological impairment after acute IS demonstrated that, compared with recombinant tissue-type plasminogen activator (rt-PA) of fibrinolysis monotherapy, patients treated with a combination of Salvianolic acid injection (Salvia miltiorrhiza-based CPM) and rt-PA may achieve better neurological recovery 24 .Collectively, these findings suggest that the integration of TCM with WM offers superior outcomes in the treatment of CI and its sequelae, without increasing adverse events.
Among the commonly prescribed MI-CPM, TCMs such as Salvia miltiorrhiza, Ginkgo, Panax notoginseng, Gastrodia, and Ligusticum Wallichii are frequently observed.These TCMs have a rich historical background in treating CI and have been extensively researched for their traditional medical principles and clinical efficacy.
Salvia miltiorrhiza possesses various pharmacological activities, including anti-atherosclerotic, anti-diabetic, anti-inflammatory, anti-oxidative and anti-tumor effects 25 .Salvia miltiorrhiza contains lipophilic constituents (tanshinone I, tanshinone IIa, tanshinone IIb, cryptotanshinone, dihydrotanshinone, etc.), as well as hydrophilic constituents (salvianolic acid A and B, danshensu, protocatechuic aldehyde, etc.) 26 .For example, tanshinone IIA exerts cardiovascular protection by reducing intimal thickening, inhibiting vascular smooth muscle cell proliferation and migration, and preventing thrombosis [27][28][29] .Cryptotanshinone (CPT) has shown anti-inflammatory and neuroprotective effects in mouse models of Alzheimer's disease (AD) by significantly reducing the expression of S100β, GFAP, COX-2, iNOS, and NFkBp65 30 .CPT also acts as an effective coronary dilator, improving microcirculation and increasing vascular blood flow 31 .Salvia miltiorrhiza hydrophilic extract has been found to significantly reduce the level of oxidized low-density lipoprotein (OX-LDL) in diabetes patients with coronary heart disease, potentially protecting against the development of diabetic cardiovascular disease 32 .Salvia miltiorrhiza injection antioxidant therapy has been shown to effectively reduce myocardial injury in children with congenital heart disease and reduce postoperative imbalance of vasoactive mediators 33 .
Ginkgo biloba has been found to potentially enhance memory and cognitive function in patients with Alzheimer's disease (AD) or Parkinson's disease (PD).This is due to its pharmacological properties including antiapoptotic, anti-oxidative, and anti-inflammatory effects 34 .Ginkgo biloba mainly contains flavonoids (such as quercetin, kaempferol, isorhamnetine) and several terpene trilactones (such as ginkgolides, bilobalide) 35 .Extract of Gingko biloba has shown significant neuroprotective effects against experimental focal cerebral ischemia 36 .Diterpene ginkgolides have been found to counteract astrocyte-mediated demyelination via the PAF-PAFR pathway 37 .Quercetin has a protective effect in the treatment of neurodegenerative and cerebrovascular diseases by inhibiting the NF-κB signaling pathway and regulating multiple kinase signaling cascades 38 .Animal studies proved that isorhamnetin can improve neurological function, enhance cognition and memory, and reduce the volume of cerebral infarction 39 .Clinical studies have demonstrated the efficacy of Ginkgo biloba extract containing ginkgolides A, B, and K, in improving neurological function in patients with IS 37 .Furthermore, quercetin supplements (500 mg/day) for 8 weeks have been found to significantly increase total antioxidant capacity in patients after myocardial infarction 40 .Diterpene ginkgolides meglumine injection has shown promising efficacy in improving functional outcome, neurological function and daily activities in patients with IS.It can be considered as an effective treatment option for elderly patients with IS 41 .
Panax notoginseng has various pharmacological activities.It has been found to have beneficial effects on the cardiovascular and immune systems.The mechanism of actions include anti-atherosclerotic, hemostatic, anticoagulant, anti-oxidative, anti-inflammatory, and neuroprotective effects 42 .The main active components of Panax notoginseng are saponins, such as Ginsenoside Rg1, Ginsenoside Rb1, and Notoginsenoside R1.Panax notoginseng saponins (PNSs) have been shown to improve angiogenesis and microperfusion, as well as protect nerves 43,44 .They have demonstrated strong therapeutic effects on cardiovascular and cerebrovascular diseases, such as atherosclerosis, cerebral hemorrhage, and cerebral ischemic injury 44,45 .Ginsenoside Rb1 has been found to improve cognitive and sensorimotor deficits in stroke rats.This improvement is achieved by modulating the Akt/mTOR/PTEN signaling pathway and down-regulating caspase-3 46 .PNSs, including Ginsenoside Rg1 and Rb1, have also been shown to inhibit the apoptosis of hippocampal cells by scavenging ROS, increasing the expression of Trx-1, SOD-1 and HSP70, and restoring the anti-apoptotic Akt-NF-B signaling pathway 47 .Notoginsenoside R1 has been found to alleviate neuronal injury induced by β-amyloid through the inhibition of reactive oxygen species and regulating MAPK activation 48 .Study has shown that Panax notoginseng saponins significantly increase the probability of functional independence at 3 months in patients with IS, suggesting that this may be a safe and effective alternative treatment to improve the prognosis of this population 49 .
Gastrodia has various effects on the nervous system, cardiovascular system, and cerebrovascular system.It has been found to provide neuronal protection and regeneration, as well as treatment for neurodegenerative diseases.Additionally, it has sedative, hypnotic, analgesic, and anti-epileptic properties.In terms of the cardiovascular and cerebrovascular system, Gastrodia exhibits cardioprotective and cerebroprotective properties, along with the ability to effectively reduce blood pressure, lower blood sugar levels, and inhibit platelet aggregation 50 .The main active constituents of Gastrodia are gastrodin, its aglycone gastrodigenin, and polysaccharides 51,52 .Gastrodin exerts therapeutic effects on central nervous system diseases by regulating neurotransmitters, inhibiting microglia activation, up-regulating neurotrophic factors, and regulating mitochondrial cascade reactions 53 .In clinical practice, Gastrodia has been used to treat cognitive deficits and prevent neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia (VD) 54 .Clinical studies have shown that gastrodin effectively reduces the incidence of postoperative neurocognitive decline in patients undergoing cardiopulmonary bypass 55 , suggesting that gastrodin is a safe and effective in the prevention of neurocognitive decline.
The pharmacological effects of Ligusticum Wallichii primarily focus on the cardiovascular and cerebrovascular systems, providing neuroprotective, antioxidative, anti-inflammatory, anti-injury, and anti-tumor effects 56 .The bioactive components found in Ligusticum Wallichii can be categorized into four groups: phenols and organic acids (e.g.ferulic acid), phthalides (e.g.ligustilide, senkyunolide A), alkaloids (e.g.tetramethylpyrazine), and polysaccharides 56 .Administration of ligustilide effectively alleviates brain tissue ischemic damage through the Nrf2 and HSP70 signaling pathways 57 .Ligusticum Wallichii is clinically indicated for conditions related to the cardiovascular, cerebrovascular, nervous, and respiratory systems 58 .Clinical studies have shown that ferulic acid supplementation reduces total cholesterol, triglycerides, and HDL-C levels in patients with hyperlipidemia.It also significantly decreases oxidative stress biomarker malondialdehyde and inflammatory marker high sensitivity-C reactive protein (hs-CRP).These findings suggest that ferulic acid supplementation improves lipid profile, oxidative stress, OX-LDL cholesterol, and inflammation in patients with hyperlipidemia.Therefore, ferulic acid has the potential to reduce the risk factors associated with cardiovascular disease 59  In addition to CPMs, WMs were also used to treat the sequelae of CI in this study.The results imply that the WMs chosen by Internet doctors to treat sequelae of CI mainly play roles in two aspects.One category is drugs that can reduce risk factors, such as anti-hypertensives, lipid-lowering agents, and antidiabetics.The other category consists of drugs targeted at treating CI, including drugs that benefit blood vessels, mainly anti-thrombotic, vasodilators, and microcirculation-improving drugs, as well as drugs for treating and nourishing cerebral nerves, covering anti-dementia agents, psychiatric/neurological agents, and cerebral metabolism-enhancing drugs.
"2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack" 60 suggests that symptomatic treatment should be given for cardiovascular-related comorbidities, and WMs reducing cerebral infarction-related risk factors (including hypertension, hyperlipidemia, and hyperglycaemia) are commonly used.For different disease etiology, such as large artery atherosclerosis, moyamoya disease, IS caused by small vessel disease, corresponding WMs treatment should be taken.The results of this study were generally consistent with the guideline recommendations.
There are some limitations in this study.First, patients can receive medical services in both offline and online hospitals.Due to the data permissions of different medical institutions and the diversity of diseases, we were unable to obtain comprehensive data on patients.Our research mainly focuses on online medical services.Second, during the online treatment process, the same patient may be treated by a different physician at each visit, and each physician may provide the patient with different medication choices based on his or her clinical experience and clinical guidelines.Our research mainly focuses on analyzing the usage trends of the same type of drugs.Third, limited to the existing internet hospital data, this study could not deeply confirm the efficacy and side effects of these online prescriptions, which should be differentiated when applied in clinical practice.Finally, it's well known that some Chinese patent medicine have similar effects with some West medicine on the diseases.Therefore, the combined usage of Chinese patent medicine and West medicine might result in synergy effects to some extent.For example, ingredients such as notoginsenoside and tanshinone have a similar effect with calcium channel blockers, and thus need to be applied with great caution in combination.These were the limitations of this study, and the results were limited to online medication.

Conclusion
In summary, this study conducted a comprehensive analysis of online prescription patterns for Chinese patients with sequelae of cerebral infarction.CPM played a significant role in the treatment of patients with sequelae of CI.MI-CPM, including Salvia miltiorrhiza, Ginkgo biloba and Panax notoginseng as the main ingredients, were the most frequently prescribed therapy for sequelae of CI.The combination of anti-hypertensives along with Salvia miltiorrhiza-based CPM emerged as the most prevalent combination therapy.This real-world study not only offered valuable insights into the prescription pattern in Chinese patients with sequelae of CI, but also served as a scientific reference for future clinical guidelines.

Figure 1 .
Figure 1.The proportion of prescriptions composed of CPM, WM, or CPM + WM in the overall prescriptions.

Table 1 .
Clinical characteristics of patients with sequelae of cerebral infarction (n = 1,981,450).

Table 2 .
Distribution of patient's gender and age.

Table 3 .
Proportion of prescriptions in patients of different gender and age.

Table 4 .
Proportion of CPM based on the following TCM in MI-CPM prescriptions.MI-CPMs Chinese patent medicines with distinguishable main ingredients; Other TCMs included some Chinese herbal and animal medicines.
Vol.:(0123456789) Scientific Reports | (2024) 14:11962 | https://doi.org/10.1038/s41598-024-62923-1 . Current studies have primarily concentrated on investigating the mechanisms by which TCMs promote blood circulation, dissolve blood stasis, regulate neural factors, suppress oxidative stress, alleviate inflammatory , and facilitate neurological recovery.These effects are consistent with the underlying mechanisms responsible for functional impairments in sequelae of CI, and therefore demonstrate potential therapeutic effects.